Bradykinin is a linear nonapeptide Arg.sup.1 -Pro.sup.2 -Pro.sup.3 -Gly.sup.4 -Phe.sup.5 -Ser.sup.6 -Pro.sup.7 -Phe.sup.8 -Arg.sup.9 that is produced endogenously in humans and other mammals as a result of the action of kallikreins, a group of proteolytic enzymes present in most tissues and body fluids, on kininogens. Once formed, this neuropeptide apparently plays an important role in inflammatory processes. It produces a number of effects associated with pain and intimation. Observations that the kallikrein-kinin system is activated to overproduce bradykinin in pathological conditions such as septic shock, anaphylaxis, rhinitis, asthma, various forms of arthritis, and inflammatory bowel disease further support the role of this endogenous peptide as a mediator of pain and inflammation. The effects of bradykinin on the cardiovascular and respiratory systems are also notable. It causes vasodilation with a concomitant fall in blood pressure. Accordingly, it has been implicated in the pathogenesis of shock, notably septic and endotoxic shock. The potent bronchoconstriction elicited by bradykinin in animals and humans has resulted in its implication in airway inflammatory conditions such as allergic asthma and rhinitis.
As a result of the implication that increased levels of bradykinin may play a part in a number of pathological conditions, considerable research has been aimed toward the derivation of bradykinin receptor antagonism as potential therapeutic agents. The first antagonists of bradykinin to be discovered were peptide relatives of the natural peptide in which L-Pro.sup.7 was replaced by D-Phe [Vavrek, R. J. and Stewart, J. M. Peptides (1985), 6, 161-164]. Several members of this series, notably D-Arg[Hyp.sup.3, Thi.sup.5,8, D-Phe.sup.7 ]-bradykinin and Lys--Lys[Hyp.sup.3, Thi.sup.5,8, D-Phe.sup.7 ]-bradykinin have been widely studied [Abe, K., Moriya, H. and Fuji, S., Eds. Adv. Exp. Med. Biol. (1989), Plenum Press, New York; Griesbacher, T. and Lembeck, F. Br. J. Pharmacol. (1987) 92,333-340; Steranka, L. R. et al. Proc. Natl. Acad. Sci. USA (1988), 55, 3245-3249]. Typically, these bradykinin antagonist peptides had Ki values in the range of 20-80 .mu.M in guinea pig ileum [Stewart, J. M. and Vavrek, R. J. In Bradykinin Antagonists: Basic and Clinical Research (1991). Burch, R. M., Ed., Marcel Dekker, New York].
Subsequently, several classes of bradykinin antagonist peptides with 600-to 1,000-fold greater potency in the guinea pig ileum preparation were disclosed. One such class consists of the initial type of bradykinin antagonist peptides in which two molecules are dimerized via a bis-succinimidohexane cross-link attached to the amino acid residue in position 6 of each of the monomeric peptides. The peptide derived by cross linking two D-Arg [Hyp.sup.3, Cys.sup.6, D-Phe.sup.7, Leu.sup.8 ]-bradykinin molecules in this manner is 50 to 100 times more potent than the monomer [Cheronis, J. C. et al. J. Med. Chem. (1992), 35, 1563-1572]. Another more recently described class of bradykinin antagonist peptides has the general structure Arg.sup.0 -Arg.sup.1 -Pro.sup.2 -Hyp.sup.3 -Gly.sup.4 -W.sup.5 -Ser.sup.6 -D-X.sup.7 -Y.sup.8 -Arg.sup.9 wherein W is an aromatic amino acid residue, e.g. Phe or Thi, and residues X and Y in position 7 and 8 are conformationally constrained unnatural amino acids, e.g. D-Tic (D-tetrahydroisoquinolinecarboxyl acid), Oic (octahydroindolecarboxylic acid), and Aoc (2-azabicyclo[3.3.0]octane-3-carboxylic acid). Two compounds in this class have been studied with particular intensity. These are of the indicated general structure in which W=Thi, X=D-Tic and Y=Oic (HOE 140) [Rhaleb, N. E. et al. Eur. J. Pharmacol. (1992),210, 115-120]and the one in which W=Thi, X=D-Tic and Y=L-Tic (NPC 16731) [Farmer, S. G. et al. Br. J. Pharmacol. (1991) 102,785-787].
A more recent series of bradykinin receptor antagonist peptides is novel in that it lacks the D-aromatic amino acid residue critical to the activity of the earlier described antagonists of the endogenous neuropeptide. In this group of compounds having the general bradykinin antagonist structure W (in position 5) is Phe or Thi, X (in position 8) is Tic or Oic. Two members of this series, namely D-Arg--Agr-Pro-Hyp-Gly-Phe-Ser-D-Hype(trans-SPh)-Oic-Arg (NPC 17661) and the corresponding peptide having D-Hype(transPr) in position 7 (NPC 17331) have been studied extensively. They are extremely potent bradykinin receptor antagonists [Kyle, D. J. and Burch, R. M. Curr. Opin. Invest. Drugs (1993), 2, 5-20].
A limitation of the bradykinin antagonist peptides is their lack of oral activity. Thus, these compounds must be administered parenterally, e.g. by local or topical application, by inhalation or by various routes of systemic injection. Further, peptides in general have a relatively short duration of action as a consequence of their rapid metabolic degradation. As a result, non-peptide or semi-peptide bradykinin receptor antagonists that lack the limitations of a peptide offer meaningful therapeutic advantages. To date, however, potent and selective non-peptide bradyinin receptor antagonists have not been reported. Only functional antagonism, not mediated by receptor binding, has been observed for a miscellaneous group of non-peptides [Calixto, J. B. et al. In Bradykinin Antagonists: Basic and Clinical Research (1991), Burch, R. M., Ed., Marcel Dekker, New York; Burch, R. M., Farmer, S. G. and Steranka, L. R. Med. Res. Rev. (1990), 10 237-269].